Descartes theory of sensory signalling by theoryman


									General Introduction to Sensory

                      Peter McNaughton

                                 Università di Insubria,
 Department of Pharmacology             Varese
Tennis Court Road, Cambridge
                                     11 April 2006
          CB2 1QJ
Descartes’ theory of sensory signalling
                        An early view of sensory
                        transduction, by René Descartes
                        (1644). In describing this
                        remarkably prescient hypothesis
                        Descartes says: “If for example the
                        fire (A) comes near the foot (B), the
                        minute particles of this fire, which
                        as you know move with great
                        velocity, have the power to set in
                        motion the spot of the skin of the
                        foot which they touch, and by this
                        means pulling on the delicate thread
                        (cc) they open up at the same
                        instant the pore (d e) against which
                        the delicate thread ends, just as by
                        pulling against one end of a rope
                        one makes to strike at the same
                        instant a bell which hangs at the
                        other end”
The role of chance in science
We shall compare two very
different sensory systems:

- Vision

- Somatic sensation
Receptors are specialised to
     detect particular
   sensory modalities
  stimulus intensities
Vision: rods and cones

          •Rods react slowly but with high
          •Cones respond more rapidly
Cones detect different wavelengths
   In the somatosensory system different
receptors detect different stimulus modalities
Frequency responses of two rapidly
    adapting mechanoreceptors
Receptors for warmth and cold
Receptive field size depends on receptor type
as well as on the extent of spread of terminals
How different receptors respond to real
        stimuli (Braille dots)
Receptors transduce energy of
their preferred modality into an
         electrical signal
 The first step is that the
  energy of the incoming
stimulus must be detected
Retinal absorbs single photons of light
The conformational change in retinal
drives a conformational change at the
    cytoplasmic face of rhodopsin
Amplification steps follow
 Photoreceptors amplify the signal in a G-
   protein coupled amplification cascade

One absorbed photon obstructs the passage of
 c. 1,000,000 Na+ ions in a dark-adapted rod
Closure of outer segment ion channels
      leads to hyperpolarisation
In somatosensory receptors the detector
     is often simply an ion channel
Example: ion channels activated by
          painful stimuli
All sensory receptors adapt
     Illumination causes the gain to be
reduced at each major step in photoreceptors
Somatosensory receptors can be divided
 into rapidly and slowly adapting types
Rapid adaptation depends on accessory
Particular features of pain
Nobody likes pain………
…but pain is
essential for
Twelve year old boy with complete
lack of sensitivity to pain. Note
missing digits (result of autophagy)
and ulcer on knee. People with
chronic pain insensitivity usually die
young from accidents, internal
bleeding, burns etc.

Chronic pain insensitivity is due to a
genetic defect in the TrkA receptor
which binds NGF. Pain-sensitive
nerve fibres consequently fail to
innervate their targets.
      Pain is in some ways different from other

We can fail to notice pain which in normal circumstances would
be unbearable ….
“This comes to tell you that I am alive and hearty except three fingers; but that's not
much, it might have been my head. How my fingers got knocked overboard I don't
know, but off they are, and I never missed them till I wanted them.”
Sailor from Collingwood's ship the Royal Sovereign writing to his father after the battle of

…..but pain can be felt in the absence of any stimulus

“Verily it is a thing wonderous strange and prodigious, and which will scarce be
credited, unless by such as have seen with their eyes, the patients who have many
months after the cutting away of the leg, greviously complained that they yet feel
exceeding great pain of that leg so cut off.”
Ambroise Pare, physician, 1552
                       Pain receptors

Are there specific pain receptors, or nociceptors, as postulated by
Sherrington in 1905, or does pain result from overstimulation of
normal touch etc. receptors?

In the 1960s Ed Perl recorded action potentials from single
afferent nerve fibres. He found separate classes of nerve
terminals responding only to high-threshold stimuli. Some were
myelinated Ad fibres, but many were unmyelinated C fibres.

So nociceptors do exist, as Sherrington originally proposed.
Typically they respond to a range of noxious stimuli – i.e. they
are polymodal.
How do nociceptors respond to a painful
Generator current and action potentials:
        noxious heat stimulus
What factors can excite and sensitize
Ion channels involved in nociceptor excitation
TRPV1 is an ion channel gated by heat,
         capsaicin and acid
                                proton sensors


               1 2 3 4 5                      6
binding site



Sensitization process at the peripheral
       terminal: prostaglandins
     How does PGE2 work?

Prostaglandins act via the cAMP/PKA
Sensitization process at the peripheral
         terminal: bradykinin

Bradykinin sensitizes the heat response by
   increasing current through TRPV1
   How does bradykinin work?

Bradykinin acts via the PKC pathway
  A possible future analgesic:
May have promise in e.g. multiple
  sclerosis, neuropathic pain
Acupuncture gives relief from some
         types of pain
Are we any closer to
understanding pain?

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